Although recent research suggests a link between the ratio of omega-6 (n-6) to omega-3 (n-3] fatty acids and cancer risk, the question as to whether a high n-6/n-3 ratio (>15), as found in most Western people, promotes tumorigenesis or if a balanced n-6/n-3 fatty acid ratio can reduce cancer development remains to be clarified in well-qualified experimental animal models. My lab has recently generated a novel transgenic mouse model that expresses the C. elegans fat-1 gene capable of converting n-6 to n-3 fatty acids, which is absent in wild type mice. These transgenic animals are characterized by an abundance of n-3 fatty acids and a balanced n-6/n-3 fatty acid ratio (1:1) in their tissues and organs, whereas wild type mice have a ratio of >30 when maintained on the same diet high in n-6 and deficient in n-3 fatty acids. Use of these transgenic animals can avoid potential confounding factors of diet and will provide more reliable evidence on the effects of n-3 fatty acids and n-6/n-3 ratio. Our pilot experiments showed a marked difference in tumor formation and growth of B16 melanoma between wild type and fat-1 transgenic mice. This exciting observation led us to hypothesize that a balanced n-6/n-3 fatty acid ratio may have a protective effect against cancer development, and that this anticancer effect is induced by changes in cancer-related gene expression mediated by certain eicosanoids or lipid mediators. Specific aims are: 1) To determine the tumorigenicity and metastasis of B16 melanoma cells implanted in the fat-1 transgenic and wild type mice;2) To characterize gene expression patterns of the tumor cells and stromal tissues in the fat-1 transgenic and wild type mice using a microarray technology;and 3) To determine if changes in eicosanoid biosynthesis are responsible for the effects on gene expression and tumor growth. Several approaches including microarray and lipidomics will be used to identify the involved mediators. Information derived from these studies will increase our understanding of the importance of n-3 fatty acids as well as n-6/n-3 fatty acid ratio in cancer prevention and help guide dietary advice.